Chchd10 is dispensable for myogenesis but critical for adipose browning

<jats:title>Abstract</jats:title><jats:p>The <jats:italic>Chchd10</jats:italic> gene encodes a coiled-coil-helix-coiled-coil-helix-domain containing protein predicted to function in the mitochondrion and nucleus. Mutations of <jats:italic>Chchd10</jats:italic> are associated with ALS, dementia and myopathy in humans and animal models, but how knockout of <jats:italic>Chchd10</jats:italic> (<jats:italic>Chchd10</jats:italic><jats:sup><jats:italic>KO</jats:italic></jats:sup>) affects various tissues especially skeletal muscle and adipose tissues remains unclear. Here we show that <jats:italic>Chchd10</jats:italic> expression increases as myoblasts and preadipocytes differentiate. During myogenesis, CHCHD10 interacts with TAR DNA binding protein 43 (TDP-43) in regenerating myofibers in vivo and in newly differentiated myotubes ex vivo. Surprisingly, <jats:italic>Chchd10</jats:italic><jats:sup><jats:italic>KO</jats:italic></jats:sup> mice had normal skeletal muscle development, growth and regeneration, with moderate defects in grip strength and motor performance. <jats:italic>Chchd10</jats:italic><jats:sup><jats:italic>KO</jats:italic></jats:sup> similarly had no effects on development of brown and white adipose tissues (WAT). However, <jats:italic>Chchd10</jats:italic><jats:sup><jats:italic>KO</jats:italic></jats:sup> mice had blunted response to acute cold and attenuated cold-induced browning of WAT, with markedly reduced UCP1 levels. Together, these results demonstrate that <jats:italic>Chchd10</jats:italic> is dispensable for normal myogenesis and adipogenesis but is required for normal motility and cold-induced, mitochondrion-dependent browning of adipocytes. The data also suggest that human <jats:italic>CHCHD10</jats:italic> mutations cause myopathy through a gain-of-function mechanism.</jats:p>